Although the currently approved NNRTIs (nevirapine, delavirdine, efavirenz, etrivirine) are highly potent, significant improvements in therapeutic utility are still required. A new generation of NNRTIS must be developed which will allow once per day dosing, exhibit significantly reduced toxicity, be amenable to dosing in woman of child bearing age, and possess a significantly higher genetic barrier to resistance selection. NNRTIs being developed by Tibotec (Etrivirine) and Idenix (IDX-899) appear to possess many of these promising therapeutic properties and these compounds are currently approved for use or entering Phase 3 human clinical trials. Structure-activity relationship data obtained with the pyrimidinediones indicates that a next generation pyrimidinedione may also be expected to meet and potentially exceed these necessary properties for a next generation NNRTI and a variety of initial lead compounds have been identified for further development. The pyrimidinediones are amenable to once per day dosing with plasma blood concentrations in excess of 20-times the required EC95 concentration achieved at 24 hours post-dosing. Additionally, ImQuest has initiated studies to optimize the formulation and delivery of IQP-0410 and preliminary results suggest further enhancement to this trough drug concentration. The pyrimidinediones have been dosed in mice, rats and dogs at concentrations of up to 2000 mg/kg/day without any overt or microscopic pathologic signs of toxicity suggesting that the compounds will likely be very safe in humans, and thus may be clinically useful in woman of child bearing age. Most importantly, the pyrimidinediones would be expected to possess an extremely high genetic barrier to resistance based on preliminary antiviral data against common problematic NNRTI-resistant and MDR viruses as well as the defined second mechanism of action of the pyrimidinediones. Though our current lead compound IQP-0410 appears to have favorable activity against these drug resistant strains, additional analogs have been identified with much more potency against drug resistant strains. Among the pyrimidinedione series of molecules, the apparent initial limit to resistance with NNRTI-resistance engendering mutations is approximately 100- to 200-fold since at that concentration level, the replication of NNRTI-resistant virus is suppressed through the entry inhibitory mechanism. Thus, in order to achieve high level resistance to the pyrimidinediones we have shown that multiple mutations must accumulate in the reverse transcriptase AND mutations must appear in both gp120 and gp41, enabling a high genetic barrier to resistance selection. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to define new lead therapeutic candidate compounds with the highest possible potency against NNRTI-resistant and MDR viruses. Lead compounds with greater potency against these viruses have been identified through our SAR evaluations, and these compounds will be further modified using standard medicinal chemistry to improve their activity against resistant viruses, to improve their solubility, and to improve their overall oral bioavailability. Enhanced potency of the pyrimidinediones may be achieved by identifying compounds with greater molecular flexibility allowing them to better bind to the hydrophobic NNRTI-binding pocket in the presence of NNRTI resistance-engendering mutations, as well as by identifying modifications which enhance the ability of the compounds to inhibit virus entry. Modifications which improve solubility and bioavailability are also expected to allow enhancements to our dosing regimen to drive further improvements in compound efficacy.